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Objective: Autonomic nervous system is involved at the onset of Parkinson disease (PD), and alpha-synuclein (alpha-Syn) and its phosphorylated form (p-alphaSyn) have been detected in dermal autonomic nerve fibers of PD. We assessed disease specific conformation variant of alpha-Syn immunoreactivity in cutaneous nerves and characterized skin denervation patterns in PD and atypical parkinsonism (AP). Methods: We enrolled 49 subjects, 19 with PD, 17 age-matched healthy controls, and 13 with AP. The manifestations of disease were rated on clinical scales. Skin biopsies from ankle, thigh, and neck were analyzed by immunofluorescence for p-alphaSyn, 5G4 as a conformation specific antibody to pathogenic alpha-Syn and PGP9.5 as axonal marker. Intraepidermal nerve fiber density was measured in all anatomical sites as marker of neurodegeneration. Thirteen of the 19 PD underwent a 1 year follow-up visit plus skin biopsies. Results: PD subjects displayed more severe cervical skin denervation (P < 0.03), which correlated to disease duration and worsened between initial and follow-up examination (P < 0.001). p-alphaSyn and 5G4 were equally sensitive and specific for the diagnosis of PD (area under the ROC was 0.839 for p-alphaSyn and 0.886 for 5G4). PD and AP with possible alpha-synucleinopathies share the features of marked cervical denervation and the presence of 5G4. In contrast AP with possible tauopathies were normal. Interpretation: Conformational specific forms of alpha-Syn are detectable in skin biopsy by immunofluorescence in PD, with a promising diagnostic efficiency similar to p-alphaSyn. Cervical cutaneous denervation correlates with disease duration and increases over time standing out as a potential biomarker of PD progression.

Stem cells are emerging as a therapeutic option for incurable diseases, such as Amyotrophic Lateral Sclerosis (ALS). However, critical issues are related to their origin as well as to the need to deepen our knowledge of the therapeutic actions exerted by these cells. Here, we investigate the therapeutic potential of clinical-grade human neural stem cells (hNSCs) that have been successfully used in a recently concluded phase I clinical trial for ALS patients (NCT01640067). The hNSCs were transplanted bilaterally into the anterior horns of the lumbar spinal cord (four grafts each, segments L3–L4) of superoxide dismutase 1 G93A transgenic rats (SOD1 rats) at the symptomatic stage. Controls included untreated SOD1 rats (CTRL) and those treated with HBSS (HBSS). Motor symptoms and histological hallmarks of the disease were evaluated at three progressive time points: 15 and 40 days after transplant (DAT), and end stage. Animals were treated by transient immunosuppression (for 15 days, starting at time of transplantation). Under these conditions, hNSCs integrated extensively within the cord, differentiated into neural phenotypes and migrated rostro-caudally, up to 3.77 ± 0.63 cm from the injection site. The transplanted cells delayed decreases in body weight and deterioration of motor performance in the SOD1 rats. At 40DAT, the anterior horns at L3–L4 revealed a higher density of motoneurons and fewer activated astroglial and microglial cells. Accordingly, the overall survival of transplanted rats was significantly enhanced with no rejection of hNSCs observed. We demonstrated that the beneficial effects observed after stem cell transplantation arises from multiple events that counteract several aspects of the disease, a crucial feature for multifactorial diseases, such as ALS. The combination of therapeutic approaches that target different pathogenic mechanisms of the disorder, including pharmacology, molecular therapy and cell transplantation, will increase the chances of a clinically successful therapy for ALS.